Plant polyphenols and their anti-cariogenic properties: a review

Polyphenols constitute one of the most common groups of substances in plants. Polyphenolic compounds have been reported to have a wide range of biological activities, many of which are related to their conventional antioxidant action; however, increasing scientific knowledge has highlighted their potential activity in preventing oral disease, including the prevention of tooth decay. The aim of this review is to show the emerging findings on the anti-cariogenic properties of polyphenols, which have been obtained from several in vitro studies investigating the effects of these bioactive molecules against Streptococcus mutans, as well as in vivo studies. The analysis of the literature supports the anti-bacterial role of polyphenols on cariogenic streptococci, suggesting (1) a direct effect against S. mutans; (2) an interaction with microbial membrane proteins inhibiting the adherence of bacterial cells to the tooth surface; and (3) the inhibition of glucosyl transferase and amylase. However, more studies, particularly in vivo and in situ, are necessary to establish conclusive evidence for the effectiveness and the clinical applications of these compounds in the prevention of dental caries. It is essential to better determine the nature and distribution of these compounds in our diet and to identify which of the hundreds of existing polyphenols are likely to provide the greatest effects.     

Flavonoids: A Myth or a Reality for Cancer Therapy?

Nutraceuticals are biologically active molecules present in foods; they can have beneficial effects on health, but they are not available in large enough quantities to perform this function. Plant metabolites, such as polyphenols, are widely diffused in the plant kingdom, where they play fundamental roles in plant development and interactions with the environment. Among these, flavonoids are of particular interest as they have significant effects on human health. In vitro and/or in vivo studies described flavonoids as essential nutrients for preventing several diseases. They display broad and promising bioactivities to fight cancer, inflammation, bacterial infections, as well as to reduce the severity of neurodegenerative and cardiovascular diseases or diabetes. Therefore, it is not surprising that interest in flavonoids has sharply increased in recent years. More than 23,000 scientific publications on flavonoids have described the potential anticancer activity of these natural molecules in the last decade. Studies, in vitro and in vivo, show that flavonoids exhibit anticancer properties, and many epidemiological studies confirm that dietary intake of flavonoids leads to a reduced risk of cancer. This review provides a glimpse of the mechanisms of action of flavonoids on cancer cells.     

Bioactivity of Two Polyphenols Quercetin and Fisetin against Human Gastric Adenocarcinoma AGS Cells as Affected by Two Coexisting Proteins

It is recognized that minor dietary components polyphenols have anticancer effects on digestive tract, lung, leukemia, and other cancers, while polyphenols also can covalently or noncovalently interact with major dietary components proteins such as casein, soybean proteins, whey proteins, and bovine serum albumin. Thus, whether the noncovalent interaction between the molecules of two polyphenols (quercetin and fisetin) and two proteins (bovine serum albumin and casein) has positive or negative impact on anticancer activities of the polyphenols against human gastric adenocarcinoma AGS cells was assessed in this study. The two polyphenols had obvious anticancer activities to the cells, because dose levels as low as 20–160 μmol/L caused reduced cell viability of 30.0–69.4% (quercetin) and 24.6–63.1% (fisetin) (using a cell treatment time of 24 h), or 9.9–48.6% (quercetin) and 6.4–29.9% (fisetin) (using a cell treatment time of 48 h). However, the cell treatments by the polyphenols in the presence of the two proteins mostly caused lower polyphenol activity toward the cells, compared with those treatments by the polyphenols in the absence of the proteins. Specifically, the presence of the proteins led to reduced growth inhibition in the cells, because higher cell viability of 33.2–86.7% (quercetin) and 29.1–77.7% (fisetin) at 24 h, or 14.1–66.8% (quercetin) and 7.9–59.0% (fisetin) at 48 h, were measured in these treated cells. The two coexisting proteins also yielded the polyphenol-treated cells with less mitochondrial membrane potential loss, less formation of reactive oxygen species, and decreased cell apoptosis. Thus, it is highlighted that the noncovalent interaction between dietary polyphenols and proteins resulted in weakened anticancer ability for the polyphenols to the gastric cancer cells.     

Antioxidant and Pro-Oxidant Capacities as Mechanisms of Photoprotection of Olive Polyphenols on UVA-Damaged Human Keratinocytes

A wide variety of polyphenols are reported to have considerable antioxidant and skin photoprotective effects, although the mechanisms of action are not fully known. Environmentally friendly and inexpensive sources of natural bioactive compounds, such as olive mill wastewater (OMWW), the by-product of olive-oil processing, can be considered an economic source of bioactive polyphenols, with a range of biological activities, useful as chemotherapeutic or cosmeceutical agents. Green strategies, such as the process based on membrane technologies, allow to recover active polyphenols from this complex matrix. This study aims to evaluate the antioxidant, pro-oxidant, and photoprotective effects, including the underlying action mechanism(s), of the ultra-filtered (UF) OMWW fractions, in order to substantiate their use as natural cosmeceutical ingredient. Six chemically characterized UF-OMWW fractions, from Italian and Greek olive cultivar processing, were investigated for their antioxidant activities, measured by Trolox Equivalent Antioxidant Capacity (TEAC), LDL oxidation inhibition, and ROS-quenching ability in UVA-irradiated HEKa (Human Epidermal Keratinocytes adult) cultures. The photoprotective properties of UF-OMWW were assayed as a pro-oxidant-mediated pro-apoptotic effect on the UVA-damaged HEKa cells, which can be potentially involved in the carcinogenesis process. All the UF-OMWW fractions exerted an effective antioxidant activity in vitro and in cells when administered together with UV-radiation on HEKa. A pro-oxidative and pro-apoptotic effect on the UVA-damaged HEKa cells were observed, suggesting some protective actions of polyphenol fraction on keratinocyte cell cultures.     

Diclofenac Diminished the Unfolded Protein Response (UPR) Induced by Tunicamycin in Human Endothelial Cells

Diclofenac belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs), which are amongst the most frequently prescribed drugs to treat fever, pain and inflammation. Despite the presence of NSAIDs on the pharmaceutical market for several decades, epidemiological studies have shown new clinical applications of NSAIDs, and new mechanisms of their action were discovered. The unfolded protein response (UPR) activated under endoplasmic reticulum (ER) stress is involved in the pathophysiology of many diseases and may become a drug target, therefore, the study evaluated the effects of diclofenac on the tunicamycin-induced UPR pathways in endothelial cells. RT PCR analysis showed that diclofenac significantly inhibited activation of ER stress-responsive genes, i.e., CHOP/DITT3, GRP78/HSPA5 and DNAJB9. Additionally, the drug diminished the significant upregulation and release of the GRP78 protein, as evaluated using the ELISA assay, which was likely to be involved in the mechanism of the UPR activation resulting in apoptosis induction in endothelial cells. These results suggest the value of diclofenac as a factor capable of restoring the ER homeostasis in endothelial cells by diminishing the UPR.     

Polyphenols’ Cardioprotective Potential: Review of Rat Fibroblasts as Well as Rat and Human Cardiomyocyte Cell Lines Research

According to the World Health Organization, cardiovascular diseases are responsible for 31% of global deaths. A reduction in mortality can be achieved by promoting a healthy lifestyle, developing prevention strategies, and developing new therapies. Polyphenols are present in food and drinks such as tea, cocoa, fruits, berries, and vegetables. These compounds have strong antioxidative properties, which might have a cardioprotective effect. The aim of this paper is to examine the potential of polyphenols in cardioprotective use based on in vitro human and rat cardiomyocytes as well as fibroblast research. Based on the papers discussed in this review, polyphenols have the potential for cardioprotective use due to their multilevel points of action which include, among others, anti-inflammatory, antioxidant, antithrombotic, and vasodilatory. Polyphenols may have potential use in new and effective preventions or therapies for cardiovascular diseases, yet more clinical studies are needed.     

EFFECTS OF PHOTODYNAMIC TREATMENT OF PLATELETS OR ENDOTHELIAL CELLS in vitro ON PLATELET AGGREGATION

The purpose of this work was to gain insight into the role played by platelets and endothelial cells in the development of thrombogenic vascular events, observed after in vivo photodynamic therapy (PDT), by studying the in vitro effects of PDT on isolated human platelets and cultured human and bovine endothelial cells. Exposure to Photofrin II (PII) and light caused platelets to rapidly lose their ability to aggregate. Photofrin II alone at high concentrations also exerted inhibitory effects on aggregation. Endothelial cells exposed to PII- and phthalocyanine (GaCl-PcS2,3 or Zn-PCS1,2)-mediated PDT released potent platelet anti- and disaggregating activity which could be identified as prostacyclin by the following criteria: a close correlation between the time and dose dependent anti-aggregating effects and released 6-keto-PGF1 alpha (the spontaneous hydrolysis product of PGI2, determined by radioimmunoassay), the inhibition of these effects by indomethacin, accumulation of 6-keto-PGF1 alpha metabolite in the media of cells treated with PDT (as determined by HPLC analysis), and the absence of evidence for significant nitric oxide production. This prostacyclin release occurred following plasma membrane damage. Although no pro-aggregating activity was observed, endothelial cells were found to release considerable amounts of arachidonic acid and prostaglandin F2 alpha in response to PDT. These data, which indicate powerful anti-thrombogenic effects in vitro, are in sharp contrast to the vascular effects of PDT in vivo which are characterized by severe platelet aggregation, and imply that the in vivo effects involve additional components of the vascular system.     

Beneficial Effects of Epigallocatechin-3-O-Gallate,Chlorogenic Acid,Resveratrol, and Curcumin on Neurodegenerative Diseases

Many observational and clinical studies have shown that consumption of diets rich in plant polyphenols have beneficial effects on various diseases such as cancer, obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases (NDDs). Animal and cellular studies have indicated that these polyphenolic compounds contribute to such effects. The representative polyphenols are epigallocatechin-3-O-gallate in tea, chlorogenic acids in coffee, resveratrol in wine, and curcumin in curry. The results of human studies have suggested the beneficial effects of consumption of these foods on NDDs including Alzheimer’s and Parkinson’s diseases, and cellular animal experiments have provided molecular basis to indicate contribution of these representative polyphenols to these effects. This article provides updated information on the effects of these foods and their polyphenols on NDDs with discussions on mechanistic aspects of their actions mainly based on the findings derived from basic experiments.     

HMG-CoA Reductase Inhibitor Regulates Endothelial Progenitor Function Through the Phosphatidylinositol 3′-Kinase/AKT Signal Transduction Pathway

HMG-CoA reductase inhibitor (statins) are known to have pleiotropic effects. We examined the effect and mechanism of simvastatin on peripheral endothelial progenitor cells (EPCs). Rats were divided into simvastatin group and the control group after cardiac infarction operation. Simvastatin treatment significantly increased the number of peripheral blood CD34+ CD133+ cells, and serum concentration of vascular endothelial growth factor (VEGF) and AKT was markedly increased in vivo. In cultured EPC, simvastatin increased the concentrations of VEGF, AKT and eNOS. Western blots analysis showed that simvastatin increased the phosphorylation of eNOS and FKHRL1, which can be blocked by the PI3K/AKT pathway blocker LY294002 . Our study demonstrated that simvastatin increases the mobilization of EPCs after cardiac infarction. In in vitro study, simvastatin increases the phosphorylation of eNOS and of FKHRL1 through the PI3K/AKT signaling pathway.     

Potential Effect of Polyphenolic-Rich Fractions of Corn Silk on Protecting Endothelial Cells against High Glucose Damage Using In Vitro and In Vivo Approaches

Endothelial cell dysfunction is considered to be one of the major causes of vascular complications in diabetes. Polyphenols are known as potent antioxidants that can contribute to the prevention of diabetes. Corn silk has been reported to contain polyphenols and has been used in folk medicine in China for the treatment of diabetes. The present study aims to investigate the potential protective role of the phenolic-rich fraction of corn silk (PRF) against injuries to vascular endothelial cells under high glucose conditions in vitro and in vivo. The protective effect of PRF from high glucose toxicity was investigated using human umbilical vein endothelial cells (HUVECs). The protective effect of PRF was subsequently evaluated by using in vivo methods in streptozotocin (STZ)-induced diabetic rats. Results showed that the PRF significantly reduced the cytotoxicity of glucose by restoring cell viability in a dose-dependent manner. PRF was also able to prevent the histological changes in the aorta of STZ-induced diabetic rats. Results suggested that PRF might have a beneficial effect on diabetic patients and may help to prevent the development and progression of diabetic complications such as diabetic nephropathy and atherosclerosis.     

Propolis Extract and Its Bioactive Compounds—From Traditional to Modern Extraction Technologies

Propolis is a honeybee product known for its antioxidant, anti-inflammatory, anticancer, and antimicrobial effects. It is rich in bioactive molecules whose content varies depending on the botanical and geographical origin of propolis. These bioactive molecules have been studied individually and as a part of propolis extracts, as they can be used as representative markers for propolis standardization. Here, we compare the pharmacological effects of representative polyphenols and whole propolis extracts. Based on the literature data, polyphenols and extracts act by suppressing similar targets, from pro-inflammatory TNF/NF-κB to the pro-proliferative MAPK/ERK pathway. In addition, they activate similar antioxidant mechanisms of action, like Nrf2-ARE intracellular antioxidant pathway, and they all have antimicrobial activity. These similarities do not imply that we should attribute the action of propolis solely to the most representative compounds. Moreover, its pharmacological effects will depend on the efficacy of these compounds’ extraction. Thus, we also give an overview of different propolis extraction technologies, from traditional to modern ones, which are environmentally friendlier. These technologies belong to an open research area that needs further effective solutions in terms of well-standardized liquid and solid extracts, which would be reliable in their pharmacological effects, environmentally friendly, and sustainable for production.     

Could Polyphenols Really Be a Good Radioprotective Strategy?

Currently, radiotherapy is one of the most effective strategies to treat cancer. However, deleterious toxicity against normal cells indicate for the need to selectively protect them. Reactive oxygen and nitrogen species reinforce ionizing radiation cytotoxicity, and compounds able to scavenge these species or enhance antioxidant enzymes (e.g., superoxide dismutase, catalase, and glutathione peroxidase) should be properly investigated. Antioxidant plant-derived compounds, such as phenols and polyphenols, could represent a valuable alternative to synthetic compounds to be used as radio-protective agents. In fact, their dose-dependent antioxidant/pro-oxidant efficacy could provide a high degree of protection to normal tissues, with little or no protection to tumor cells. The present review provides an update of the current scientific knowledge of polyphenols in pure forms or in plant extracts with good evidence concerning their possible radiomodulating action. Indeed, with few exceptions, to date, the fragmentary data available mostly derive from in vitro studies, which do not find comfort in preclinical and/or clinical studies. On the contrary, when preclinical studies are reported, especially regarding the bioactivity of a plant extract, its chemical composition is not taken into account, avoiding any standardization and compromising data reproducibility.     

Simultaneous ultrasound-assisted water extraction and β-cyclodextrin encapsulation of polyphenols from Mangifera indica stem bark in counteracting TNFα-induced endothelial dysfunction

This study proposes an alternative technique to prevent heat degradation induced by classic procedures of bioactive compound extraction, comparing classical maceration/decoction in hot water of polyphenols from Mango (Mangifera indica L.) (MI) with ultrasound-assisted extraction (UAE) in a water solution of β-cyclodextrin (β-CD) at room temperature and testing their biological activity on TNFα-induced endothelial dysfunction. Both extracts counteracted TNFα effects on EAhy926 cells, down-modulating interleukin-6, interleukin-8, cyclooxygenase-2 and intracellular adhesion molecule-1, while increasing endothelial nitric oxide synthase levels. β-CD extract showed higher efficacy in improving endothelial function. These effects were abolished after pre-treatment with the oestrogen receptor inhibitor ICI1182,780. Moreover, the β-CD extract induced Akt activation and completely abolished the TNFα-induced p38MAPK phosphorylation. UAE and β-CD encapsulation provide an efficient extraction protocol that increases polyphenol bioavailability. Polyphenols from MI play a protective role on endothelial cells and may be further considered as oestrogen-like molecules with vascular protective properties.     

UPLC–Q–TOF–MS/MS Analysis of Phenolic Compounds from the Fruit of Cephalostachyum fuchsianum Gamble and Their Antioxidant and Cytoprotective Activities

Bamboo is a widely distributed graminaceous plant in China and is a potential source of bioactive substances. Incidentally, bamboo’s fruit is rich in phytochemicals such as polyphenols and flavonoids, which are significant to human health. In this study, we identified the phenolic compounds of the fruit and investigated the antioxidant activities of Cephalostachyum fuchsianum Gamble (CFG) fruit polyphenols with in vitro and in vivo tests for the first time. UPLC–Q–TOF–MS/MS analysis results showed that the fruit contained 43 phenolic compounds, including 7 hydroxybenzoic acids, 12 flavonoids, 7 coumarins, 10 hydroxycinnamic acids, 1 terpenoid, and 5 lignans. The TPC of SP extracts was higher than that of IBPs extracts in FP and FF. The SP extracts in FP showed better antioxidant activities in vitro compared to those in FF. In addition, polyphenols from CFG fruits protected against H₂O₂-induced oxidative damage in HepG2 cells, and the protective effect of polyphenols in FP was superior to that in FF. The analysis results showed that CFG fruit has great potential in exploiting natural chemical substances, which can provide valuable pieces of information for the further development and utilization of CFG.     

Plant phenolics: extraction, analysis and their antioxidant and anticancer properties

Phenolics are broadly distributed in the plant kingdom and are the most abundant secondary metabolites of plants. Plant polyphenols have drawn increasing attention due to their potent antioxidant properties and their marked effects in the prevention of various oxidative stress associated diseases such as cancer. In the last few years, the identification and development of phenolic compounds or extracts from different plants has become a major area of health- and medical-related research. This review provides an updated and comprehensive overview on phenolic extraction, purification, analysis and quantification as well as their antioxidant properties. Furthermore, the anticancer effects of phenolics in-vitro and in-vivo animal models are viewed, including recent human intervention studies. Finally, possible mechanisms of action involving antioxidant and pro-oxidant activity as well as interference with cellular functions are discussed.     

Mealworm Oil (MWO) Enhances Wound Healing Potential through the Activation of Fibroblast and Endothelial Cells

Mealworm and mealworm oil (MWO) have been reported to affect antioxidant, anti-coagulation, anti-adipogenic and anti-inflammatory activities. However, the function of MWO in wound healing is still unclear. In this study, we found that MWO induced the migration of fibroblast cells and mRNA expressions of wound healing factors such as alpha-smooth muscle actin (α-SMA), collagen-1 (COL-1) and vascular endothelial growth factor (VEGF) in fibroblast cells. The tube formation and migration of endothelial cells were promoted through the activation of VEGF/VEGF receptor-2 (VEGFR-2)-mediated downstream signals including AKT, extracellular signal-regulated kinase (ERK) and p38 by MWO-stimulated fibroblasts for angiogenesis. Moreover, we confirmed that MWO promoted skin wound repair by collagen synthesis, re-epithelialization and angiogenesis in an in vivo excisional wound model. These results demonstrate that MWO might have potential as a therapeutic agent for the treatment of skin wounds.     

The Intervention of Prebiotics on Depression via the Gut–Brain Axis

The imbalance of intestinal microbiota can cause the accumulation of endotoxin in the main circulation system of the human body, which has a great impact on human health. Increased work and life pressure have led to a rise in the number of people falling into depression, which has also reduced their quality of life. The gut–brain axis (GBA) is closely related to the pathological basis of depression, and intestinal microbiota can improve depressive symptoms through GBA. Previous studies have proven that prebiotics can modulate intestinal microbiota and thus participate in human health regulation. We reviewed the regulatory mechanism of intestinal microbiota on depression through GBA, and discussed the effects of prebiotics, including plant polysaccharides and polyphenols on the regulation of intestinal microbiota, providing new clues for the prevention and treatment of depression.     

Chondroprotection and Molecular Mechanism of Action of Phytonutraceuticals on Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease and an important cause of incapacitation. There is a lack of drugs and effective treatments that stop or slow the OA progression. Modern pharmacological treatments, such as analgesics, have analgesic effects but do not affect the course of OA. Long-term use of these drugs can lead to serious side effects. Given the OA nature, it is likely that lifelong treatment will be required to stop or slow its progression. Therefore, there is an urgent need for disease-modifying OA treatments that are also safe for clinical use over long periods. Phytonutraceuticals are herbal products that provide a therapeutic effect, including disease prevention, which not only have favorable safety characteristics but may have an alleviating effect on the OA and its symptoms. An estimated 47% of OA patients use alternative drugs, including phytonutraceuticals. The review studies the efficacy and action mechanism of widely used phytonutraceuticals, analyzes the available experimental and clinical data on the effect of some phytonutraceuticals (phytoflavonoids, polyphenols, and bioflavonoids) on OA, and examines the known molecular effect and the possibility of their use for chondroprotection.     

Pharmacological and Therapeutic Properties of Punica granatum Phytochemicals: Possible Roles in Breast Cancer

Background: Pomgranate (Punica granatum) represents a high source of polyphenols with great bioavailability. The role of this fruit in the prevention and treatment of various malignant pathologies has been long time cited in both scientific and non-scientific literature, making thus important to identify its involvement in the pathophysiological processes. The treatment for breast cancer had focused on the inhibition of the mechanisms that governs the estrogen activity. These mechanisms are covered either by the antagonism of the estrogen receptor (ER) or by the inhibition of the estrogen synthesis. Our interest in identifying a bioactive compound rich in polyphenols, which induces both the antagonism of the estrogen receptor, and the inhibition of the estrogen synthesis, revealed us the pomegranate fruit and its derivatives: peel and seeds. Pomegranates’ chemical composition include many biological active substances such as flavonols, flavanols, anthocyanins, proanthocyanidins, ellagitannins and gallotannins. Materials and Methods: We performed a review of the scientific literature by using the following keywords: “pomegranate”, “breast cancer”, “Punica granatum”, “pomegranate polyphenols”. Our search was performed in the PubMed and Google Scholar databases, and it included only original research written in English from the last 20 years. None of the articles were excluded due to affiliation. A total number of 28 original papers, which mentioned the beneficial activity of pomegranate against breast cancer, were selected. Both clinical and preclinical studies were considered for this review. Results: Recent discoveries pointed out that polyphenols from Punica granatum possess strong anti-cancer activity, exhibited by a variety of mechanisms, such as anti-estrogenic, anti-proliferative, anti-angiogenetic, anti-inflammatory, and anti-metastatic. Pomegranate extracts induced cell cycle arrest in the G0/G1 phase, and induced cytotoxicity in a dose- and time-dependent manner. Moreover, several polyphenols extracted from pomegranate inhibited the invasion potential, migration and viability of breast cancer cells. The effects of pomegranate juice on serum estrogens and other sexual hormones levels were also investigated on two human cohorts. Conclusions: Punica granatum represents a promising area in oncology. The large availability and low cost, associated with the lack of side effects, made from this natural product a great strategy for the management of breast cancer. There are several mechanistic studies in mouse models and in breast cancer cell lines, suggesting the possible pathways through which polyphenols from pomegranate extracts act, but larger and better-controlled studies are necessary in the future. Only two small clinical trials were conducted on humans until now, but their results are contradictory and should be considered preliminary.